(-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake inhibitor

ABSTRACT

The present invention relates to (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof, compositions comprising (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof, and methods for treating or preventing a disorder alleviated by inhibiting dopamine reuptake. In one embodiment, the disorder is attention-deficit disorder, depression, obesity, Parkinson&#39;s disease, a tic disorder, or an addictive disorder. The (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or pharmaceutically acceptable salt thereof is preferably substantially free of its corresponding (+)-enantiomer.

This application is a divisional of application Ser. No. 10/425,545,filed on Apr. 29, 2003, now U.S. Pat. No. 6,716,868 which is adivisional of application Ser. No. 09/939,071, filed on Aug. 24, 2001,now U.S. Pat. No. 6,569,887, dated May 27, 2003.

1. FIELD OF THE INVENTION

The present invention relates to(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof, compositions comprising(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof and methods for treating orpreventing a disorder alleviated by inhibiting dopamine reuptakecomprising administering to a patient(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof.

2. BACKGROUND OF THE INVENTION

Dopamine is a monoamine neurotransmitter that plays a critical role inthe function of the hypothalamic-pituitary-adrenal axis and in theintegration of information in sensory, limbic, and motor systems. Theprimary mechanism for termination of dopamine neurotransmission isthrough reuptake of released dopamine by Na⁺/Cl⁻-dependent plasmamembrane transporters (Hoffman et al., 1998, Front. Neuroendocrinol.19(3):187–231). Depending on the surrounding ionic conditions, thedopamine transporter can function as a mediator of both inward directeddopamine transport (i.e., “reuptake”) and outward directed dopaminetransport (i.e., “release”). The functional significance of the dopaminetransporter is its regulation of dopamine neurotransmission byterminating the action of dopamine in a synapse via reuptake (Hitri etal., 1994, Clin. Pharmacol. 17:1–22).

Attention deficit disorder is a learning disorder involvingdevelopmentally inappropriate inattention with or without hyperactivity.The primary signs of attention deficit disorder are a patient'sinattention and impulsivity. Inappropriate inattention causes increasedrates of activity or reluctance to participate or respond. A patientsuffering from attention deficit disorder exhibits a consistent patternof inattention and/or hyperactivity-impulsivity that is more frequentand severe than is typically observed in individuals at a comparablelevel of development. (See, e.g., U.S. Pat. No. 6,121,261 to Glatt etal.).

Patients having Parkinson's disease display jittery movements of thelimbs, head, and jaw. Parkinson's disease is associated withbradykinesia, rigidity and falling (Stacy et al., 1996, Am. Fam. Phys.53:1281–1287). The movement disturbances observed in Parkinson's diseasepatients result from degeneration of dopamine neurons, loss of nerveterminals, and dopamine deficiency. It is hypothesized that the cause ofthe degeneration of the dopamine neurons results from apoptosisresulting from increased levels of cytokines (Nagatsu et al., 2000, J.Neural Transm. Suppl. 60:277–290). Abnormalities in the dopaminetransporter have been implicated in Parkinson's disease (Hitri et al.,1994, Clin. Neuropharmacol. 17:1–22). Symptoms of Parkinson's diseasecan be attenuated by compounds like pergolide which mimics the actionsof dopamine or by compounds that inhibit dopamine metabolism (e.g.,carbidopa) or by dopamine precursors (e.g., L-DOPA±carbidopa).

Appetite suppression is a reduction, a decrease or, in cases ofexcessive food consumption, an amelioration in appetite. Thissuppression reduces the desire or craving for food. Appetite suppressioncan result in weight loss or weight control as desired. Appetitesuppression can regulate food intake through drug administrationdirected to one or more systems known to play a role in food digestion.See, for example, Sullivan et al., “Mechanisms of Appetite Modulation ByDrugs,” Federation Proceedings, Volume 44, No. 1, Part 1, pages 139–144(1985). Methods for controlling appetite suppression include theregulation of serotonin level, thermogenesis and the inhibition oflipogenesis. (See e.g., U.S. Pat. No. 5,911,992 to Braswell et al.).

Depression is one of the most common of the mental illnesses, having amorbidity rate of over 10% in the general population. Depression ischaracterized by feelings of intense sadness, despair, mental slowing,loss of concentration, pessimistic worry, agitation, andself-deprecation (Harrison 's Principles of Internal Medicine 2490–2497(Fauci et al. eds., 14^(th) ed. 1998)). Depression can have physicalmanifestations including insomnia, hypersomnia, anorexia, weight loss,overeating, decreased energy, decreased libido, and disruption of normalcircadian rhythms of activity, body temperature, and endosine functions.In fact, as many as 10% to 15% of depressed individuals display suicidalbehavior. R. J. Baldessarini, Drugs and the Treatment of PsychiatricDisorders: Depression and Mania, in Goodman and Gilman's ThePharmacological Basis of Therapeutics 431 (9^(th) ed. 1996). Anhedoniais one of the principal (core) symptoms of depression. Dopamine pathwayshave been linked to pleasure seeking behaviors, and strategies toincrease synaptic concentrations of dopamine have been proposed asantidepressant therapies. (See e.g., D'Aquila et al., 2000, Eur. J.Pharmacol. 405:365–373).

Obesity is commonly referred to as a condition of increased body weightdue to excessive fat. Drugs to treat obesity can be divided into threegroups: (1) those that decrease food intake, such as drugs thatinterfere with monoamine receptors, such as noradrenergic receptors,serotonin receptors, dopamine receptors, and histamine receptors; (2)those that increase metabolism; and (3) those that increasethermogenesis or decrease fat absorption by inhibiting pancreatic lipase(Bray, 2000, Nutrition 16:953–960 and Leonhardt et al., 1999, Eur. J.Nutr. 38:1–13).

Many drugs can cause physical and/or psychological addiction. Those mostwell known drugs include opiates, such as heroin, opium and morphine;sympathomimetics, including cocaine and amphetamines;sedative-hypnotics, including alcohol, benzodiazepines and barbiturates;and nicotine, which has effects similar to opioids and sympathomimetics.Drug addiction is characterized by a craving or compulsion for takingthe drug and an inability to limit its intake. Additionally, drugdependence is associated with drug tolerance, the loss of effect of thedrug following repeated administration, and withdrawal, the appearanceof physical and behavioral symptoms when the drug is not consumed.Sensitization occurs if repeated administration of a drug leads to anincreased response to each dose. Tolerance, sensitization, andwithdrawal are phenomena evidencing a change in the central nervoussystem resulting from continued use of the drug. This change motivatesthe addicted individual to continue consuming the drug despite serioussocial, legal, physical and/or professional consequences. (See, e.g.,U.S. Pat. No. 6,109,269 to Rise et al.). Cocaine addiction remains oneof the major health problems in the United States. Fundamental studiesfrom many laboratories have shown that cocaine blocks the uptake ofdopamine from the synaptic cleft of the dopamine transporter (Kreek,1996, J. Addict. Dis. 15:73–96). For example, the inhibition action ofcocaine on reuptake of released dopamine, however, does not fullyexplain the development and maintenance of addictive behavior.Coexistence of functionally antagonistic, inhibition actions of cocaineon the dopamine release and reuptake of the released dopamine might beresponsible for fluctuations in dopamine transmission (Kiyatkin, 1994,Int. J. Neurosci. 78:75–101).

Certain pharmaceutical agents have been administered for treatingaddiction. U.S. Pat. No. 5,556,838 to Mayer et al. discloses the use ofnontoxic NMDA-blocking agents co-administered with an addictivesubstance to prevent the development of tolerance or withdrawalsymptoms. U.S. Pat. No. 5,574,052 to Rose et al. disclosesco-administration of an addictive substance with an antagonist topartially block the pharmacological effects of the substance. U.S. Pat.No. 5,075,341 to Mendelson et al. discloses the use of a mixed opiateagonist/antagonist to treat cocaine and opiate addiction. U.S. Pat. No.5,232,934 to Downs discloses administration of 3-phenoxypyridine totreat addiction. U.S. Pat. Nos. 5,039,680 and 5,198,459 to Imperato etal. disclose using a serotonin antagonist to treat chemical addiction.U.S. Pat. No. 5,556,837 to Nestler et. al. discloses infusing BDNF orNT-4 growth factors to inhibit or reverse neurological adaptive changesthat correlate with behavioral changes in an addicted individual. U.S.Pat. No. 5,762,925 to Sagan discloses implanting encapsulated adrenalmedullary cells into a patient's central nervous system to inhibit thedevelopment of opioid intolerance. Bupropion has dopamine reuptakeinhibition properties and is used to treat nicotine addiction.

Dopaminergic reward pathways have been implicated in disorders resultingfrom addictive behaviors. Variants of the dopamine D2 receptor gene havebeen associated with alcoholism, obesity, pathological gambling,attention deficit hyperactivity disorder, Tourette syndrome, cocainedependence, nicotine dependence, polysubstance abuse, and other drugdependency (Noble, 1994, Alcohol Supp. 2:35–43 and Blum et al., 1995,Pharmacogenetics 5:121–141). Since reduced dopaminergic functions havebeen found in individuals with a minor A1 allele of the dopamine D2receptor, it has been suggested that the dopamine D2 receptor may be areinforcement or reward gene (Noble, 1994, Alcohol Supp. 2:35–43).Furthermore, several studies suggest that an associate of dopamine D2receptor gene polymorphisms are associated withimpulsive-addictive-compulsive behavior, i.e., “Reward DeficiencySyndrome” (reviewed by Blum et al., 1995, Pharmacogenetics 5:121–141).

U.S. Pat. No. 4,435,419 to Epstein et al. discloses racemic,(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane for use as ananti-depressant agent.

U.S. Pat. No. 6,204,284 to Beer et al. discloses racemic,(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane for use in theprevention or relief of a withdrawal syndrome resulting from addition todrugs and for the treatment of chemical dependencies.

Administration of a racemic, i.e., 50:50, mixture of the (+)- and the(−)-enantiomer of any drug, for example(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, to a patient canbe disadvantageous. First, the racemic mixture might be lesspharmacologically active than one of its enantiomers, rendering racemicdrugs inherently inefficient. Second, the racemic mixture may be moretoxic to a patient than one of its enantiomers, so that administrationof a racemic mixture can lead to undesirable side effects in a patient.

Accordingly, there is a clear need in the art for an enantiomer, theenantiomer being preferably substantially free of the correspondingopposite enantiomer, which would overcome one or both of theaforementioned disadvantages.

Citation of identification of any reference in Section 2 of thisapplication is not to be construed as an admission that such referenceis prior art to the present application.

3. SUMMARY OF THE INVENTION

In one embodiment, the invention provides(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof.(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof are useful for treating orpreventing a disorder alleviated by inhibiting dopamine reuptake.

The present invention further provides compositions comprising aneffective amount of (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexaneor a pharmaceutically acceptable salt thereof. The present compositionscan additionally comprise a pharmaceutically acceptable vehicle. Thesecompositions are useful for treating or preventing a disorder alleviatedby inhibiting dopamine reuptake.

In another embodiment, the invention provides a method for treating orpreventing a disorder alleviated by inhibiting dopamine reuptake,comprising administering to a patient in need of such treatment orprevention an effective amount of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof.

In still another embodiment, the invention provides a method fortreating or preventing attention-deficit disorder, depression, obesity,Parkinson's disease, a tic disorder, or an addictive disorder,comprising administering to a patient in need of such treatment orprevention an effective amount of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof.

Preferably, (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof, particularly when used in thepresent methods or compositions, is substantially free of itscorresponding (+)-enantiomer. In a preferred embodiment,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof substantially free of itscorresponding (+)-enantiomer is used to treat or prevent a disorderalleviated by selectively inhibiting dopamine uptake. Use according tothis preferred embodiment, surprisingly and advantageously does notblock norepinephrine or serotonin transport, in particular,norepinephrine or serotonin uptake. It has unexpectedly been discoveredthat use of (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof substantially free of itscorresponding (+) enantiomer to treat or prevent a disorder alleviatedby inhibiting dopamine uptake avoids side effects such as cardiovasculareffects, sleep interruption, hypertension or sexual dysfunctionassociated with norepinephrine or serotonin uptake inhibitors.

In still another embodiment, the invention provides a method forobtaining (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexanesubstantially free of its corresponding (+)-enantiomer, comprising thesteps of:

(a) passing a solution of an organic eluent and(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane over a chiralpolysaccharide stationary phase to provide a first fraction containing(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane; and

(b) passing the first fraction over the chiral polysaccharide stationaryphase to provide a second fraction containing(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane substantially freeof its corresponding (+)-enantiomer.

In still another embodiment, the invention provides a method forobtaining (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexanesubstantially free of its corresponding (+)-enantiomer, comprising thesteps of:

(a) passing a solution of an organic eluent and(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane over a chiralpolysaccharide stationary phase to provide a first fraction containing(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane;

(b) concentrating the first fraction to provide a residue; and

(c) passing a solution of an organic eluent and the residue over achiral polysaccharide stationary phase to provide a second fractioncontaining (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexanesubstantially free of its corresponding (+)-enantiomer.

The present invention may be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION

4.1 Definitions

The term “substantially free of its corresponding (+)-enantiomer” meanscontaining no more than about 5% w/w of the corresponding(+)-enantiomer, preferably no more than about 2% w/w of thecorresponding (+)-enantiomer, more preferably no more than about 1% w/wof the corresponding (+)-enantiomer.

The term “corresponding (+)-enantiomer” when used in connection with(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof means“(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane” or apharmaceutically acceptable salt thereof.

A “patient” is an animal, including, but not limited to, an animal sucha cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog,mouse, rat, rabbit, and guinea pig, and is more preferably a mammal, andmost preferably a human.

The phrase “pharmaceutically acceptable salt” as used herein is a saltformed from an acid and the basic nitrogen group of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. Preferred saltsinclude, but not limited, to sulfate, citrate, acetate, oxalate,chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate(i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

4.2 (−)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane

(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, preferably thatsubstantially free of its corresponding (+)-enantiomer, can be obtainedfrom (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane using chiralchromatographic methods, such as high-performance liquid chromatography(“HPLC”) with a suitable, preferably chiral, column.(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane is obtainable usingmethods disclosed in U.S. Pat. No. 4,435,419 to Epstein et al.

In a preferred embodiment,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane is obtained bypassing a solution of an organic eluent and(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane over a chiralpolysaccharide stationary phase. Preferably, the polysaccharide isstarch or a starch derivative. Advantageously, the chiral stationaryphase is within a chiral HPLC column, for example, a CHIRALPAK AD columnmanufactured by Daicel and commercially available from ChiralTechnologies, Inc., Exton, Pa., more preferably a 1 cm×25 cm CHIRALPAKAD HPLC column. The preferred eluent is a hydrocarbon solvent adjustedin polarity with a miscible polar organic solvent. Preferably, theorganic eluent contains a non-polar, hydrocarbon solvent present inabout 95% to about 99.5% (volume/volume) and a polar organic solventpresent in about 5 to about 0.5% (volume/volume). In a preferredembodiment, the hydrocarbon solvent is hexane and the miscible polarorganic solvent is isopropylamine.

Passing the solution of the organic eluent and(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane over the chiralpolysaccharide stationary phase provides a first fraction (i.e., one ormore fractions) containing(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. The first fractioncan be directly passed over the chiral polysaccharide stationary phaseto provide a second fraction (i.e., one or more fractions) containing(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane substantially freeof its corresponding (+)-enantiomer. Alternatively, the first fractioncan be concentrated to provide a residue that can be diluted with anorganic eluent, and the resulting solution can be passed over the chiralpolysaccharide stationary phase to provide a second fraction containing(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane substantially freeof its corresponding (+)-enantiomer. Either way, the second fraction(s)can be concentrated, preferably in vacuo, to obtain a solid form of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane substantially freeof its corresponding (+)-enantiomer.

4.3 Therapeutic Uses of(−)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane

In accordance with the invention,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is administered to a patient,preferably a mammal, more preferably a human, for the treatment orprevention of a disorder alleviated by inhibiting dopamine reuptake. Inone embodiment, “treatment” or “treating” refers to an amelioration of adisorder alleviated by inhibiting dopamine reuptake, or at least onediscernible symptom thereof. In another embodiment, “treatment” or“treating” refers to an amelioration of at least one measurable physicalparameter, not necessarily discernible by the patient. In yet anotherembodiment, “treatment” or “treating” refers to inhibiting theprogression of a disorder alleviated by inhibiting dopamine reuptake,either physically, e.g., normalization of a discernible symptom,physiologically, e.g., normalization of a physical parameter, or both.In yet another embodiment, “treatment” or “treating” refers to delayingthe onset of a disorder alleviated by inhibiting dopamine reuptake.

In certain embodiments,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is administered to a patient,preferably a mammal, more preferably a human, as a preventative measureagainst acquiring a disorder alleviated by inhibiting dopamine reuptake.As used herein, “prevention” or “preventing” refers to a reduction ofthe risk of acquiring a disorder alleviated by inhibiting dopaminereuptake or to the reduction of the risk of recurrence of the disorderonce cured or restored to a normal state. In one embodiment,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is administered as apreventative measure to a patient. According to this embodiment, thepatient can have a genetic predisposition to a disorder alleviated byinhibiting dopamine reuptake, such as a family history of biochemicalimbalance in the brain, or a non-genetic predisposition to a disorderalleviated by inhibiting dopamine reuptake. Accordingly, the (−)1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and pharmaceuticallyacceptable salts thereof can be used for the treatment of onemanifestation of a disorder alleviated by inhibiting dopamine reuptakeand prevention of another.

4.3.1 Disorders Alleviated Using(−)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane

(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof are useful for treating orpreventing endogenous disorders alleviated by inhibiting dopaminereuptake. Such disorders include, but are not limited to,attention-deficit disorder, depression, obesity, Parkinson's disease,tic disorders, and addictive disorders.

Disorders alleviated by inhibiting dopamine reuptake are not limited tothe specific disorders described herein, as many types of disorders maymanifest from the primary disorder. For example, as disclosed in U.S.Pat. No. 6,132,724 to Blum, attention deficit hyperactivity disorder maymanifest itself in the form of alcohol abuse, drug abuse, obsessivecompulsive behaviors, learning disorders, reading problems, gambling,manic symptoms, phobias, panic attacks, oppositional defiant behavior,conduct disorder, academic problems in school, smoking, abnormal sexualbehaviors, schizoid behaviors, somatization, depression, sleepdisorders, general anxiety, stuttering, and tics disorders. All thesebehaviors and others described herein as associated with disordersalleviated by inhibiting dopamine reuptake are included as disorders aspart of this invention. Additionally, clinical terms used herein formany specific disorders are found in the Quick Reference to theDiagnostic Criteria From DSM-IV (Diagnostic and Statistical Manual ofMental Disorders, Fourth Edition), The American Psychiatric Association,Washington, D.C., 1994, 358 pages. Specific disorders whose definitionscan be found in this reference are described below.

Attention-deficit disorders include, but are not limited to,Attention-Deficit/Hyperactivity Disorder, Predominately InattentiveType; Attention-Deficit/Hyperactivity Disorder, PredominatelyHyperactivity-Impulsive Type; Attention-Deficit/Hyperactivity Disorder,Combined Type; Attention-Deficit/Hyperactivity Disorder not otherwisespecified (NOS); Conduct Disorder; Oppositional Defiant Disorder; andDisruptive Behavior Disorder not otherwise specified (NOS).

Depressive disorders include, but are not limited to, Major DepressiveDisorder, Recurrent; Dysthymic Disorder; Depressive Disorder nototherwise specified (NOS); and Major Depressive Disorder, SingleEpisode.

Parkinson's disease includes, but is not limited to, neuroleptic-inducedparkinsonism.

Addictive disorders include, but are not limited to, eating disorders,impulse control disorders, alcohol-related disorders, nicotine-relateddisorders, amphetamine-related disorders, cannabis-related disorders,cocaine-related disorders, hallucinogen use disorders, inhalant-relateddisorders, and opioid-related disorders, all of which are furthersub-classified as listed below.

Eating disorders include, but are not limited to, Bulimia Nervosa,Nonpurging Type; Bulimia Nervosa, Purging Type; and Eating Disorder nototherwise specified (NOS).

Impulse control disorders include, but are not limited to, IntermittentExplosive Disorder, Kleptomania, Pyromania, Pathological Gambling,Trichotillomania, and Impulse Control Disorder not otherwise specified(NOS).

Alcohol-related disorders include, but are not limited to,Alcohol-Induced Psychotic Disorder, with delusions; Alcohol Abuse;Alcohol Intoxication; Alcohol Withdrawal; Alcohol Intoxication Delirium;Alcohol Withdrawal Delirium; Alcohol-Induced Persisting Dementia;Alcohol-Induced Persisting Amnestic Disorder; Alcohol Dependence;Alcohol-Induced Psychotic Disorder, with hallucinations; Alcohol-InducedMood Disorder; Alcohol-Induced Anxiety Disorder; Alcohol-Induced SexualDysfunction; Alcohol-Induced Sleep Disorder; Alcohol-Related Disordernot otherwise specified (NOS); Alcohol Intoxication; and AlcoholWithdrawal.

Nicotine-related disorders include, but are not limited to, NicotineDependence, Nicotine Withdrawal, and Nicotine-Related Disorder nototherwise specified (NOS).

Amphetamine-related disorders include, but are not limited to,Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication,Amphetamine Withdrawal, Amphetamine Intoxication Delirium,Amphetamine-Induced Psychotic Disorder with delusions,Amphetamine-Induced Psychotic Disorders with hallucinations,Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced SleepDisorder, Amphetamine Related Disorder not otherwise specified (NOS),Amphetamine Intoxication, and Amphetamine Withdrawal.

Cannabis-related disorders include, but are not limited to, CannabisDependence; Cannabis Abuse; Cannabis Intoxication; Cannabis IntoxicationDelirium; Cannabis-Induced Psychotic Disorder, with delusions;Cannabis-Induced Psychotic Disorder with hallucinations;Cannabis-Induced Anxiety Disorder; Cannabis Related Disorder nototherwise specified (NOS); and Cannabis Intoxication.

Cocaine-related disorders include, but are not limited to, CocaineDependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal,Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder withdelusions, Cocaine-Induced Psychotic Disorders with hallucinations,Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder,Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder,Cocaine Related Disorder not otherwise specified (NOS), CocaineIntoxication, and Cocaine Withdrawal.

Hallucinogen-use disorders include, but are not limited to, HallucinogenDependence, Hallucinogen Abuse, Hallucinogen Intoxication, HallucinogenWithdrawal, Hallucinogen Intoxication Delirium, Hallucinogen-InducedPsychotic Disorder with delusions, Hallucinogen-Induced PsychoticDisorders with hallucinations, Hallucinogen-Induced Mood Disorder,Hallucinogen-Induced Anxiety Disorder, Hallucinogen-Induced SexualDysfunction, Hallucinogen-Induced Sleep Disorder, Hallucinogen RelatedDisorder not otherwise specified (NOS), Hallucinogen Intoxication, andHallucinogen Persisting Perception Disorder (Flashbacks).

Inhalant-related disorders include, but are not limited to, InhalantDependence; Inhalant Abuse; Inhalant Intoxication; Inhalant IntoxicationDelirium; Inhalant-Induced Psychotic Disorder, with delusions;Inhalant-Induced Psychotic Disorder with hallucinations;Inhalant-Induced Anxiety Disorder; Inhalant Related Disorder nototherwise specified (NOS); and Inhalant Intoxication.

Opioid-related disorders include, but are not limited to, OpioidDependence, Opioid Abuse, Opioid Intoxication, Opioid IntoxicationDelirium, Opioid-Induced Psychotic Disorder, with delusions,Opioid-Induced Psychotic Disorder with hallucinations, Opioid-InducedAnxiety Disorder, Opioid Related Disorder not otherwise specified (NOS),Opioid Intoxication, and Opioid Withdrawal.

Tic disorders include, but are not limited to, Tourette's Disorder,Chronic Motor or Vocal Tic Disorder, Transient Tic Disorder, TicDisorder not otherwise specified (NOS), Stuttering, Autistic Disorder,and Somatization Disorder.

4.4 Therapeutic/Prophylactic Administration and Composition of theInvention

Due to their activity,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof are advantageously useful inveterinary and human medicine. As described above,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof are useful for the treatmentor prevention of a disorder alleviated by inhibiting dopamine reuptake.

When administered to a patient,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is preferably administered ascomponent of a composition that optionally comprises a pharmaceuticallyacceptable vehicle. The present compositions, which comprise aneffective amount of (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexaneor a pharmaceutically acceptable salt thereof, are preferablyadministered orally. The compositions of the invention can also beadministered by any other convenient route, for example, by infusion orbolus injection, by absorption through epithelial or mucocutaneouslinings (e.g., oral mucosa, rectal, and intestinal mucosa, etc.) and canbe administered together with another biologically active agent.Administration can be systemic or local. Various delivery systems areknown, e.g., encapsulation in liposomes, microparticles, microcapsules,and capsules, and can be used to administer(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof.

In certain embodiments, the present compositions can comprise(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and/or one or morepharmaceutically acceptable salts thereof.

Methods of administration include but are not limited to intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravaginal,transdermal, rectally, by inhalation, or topically, particularly to theears, nose, eyes, or skin. The mode of administration is left to thediscretion of the practitioner. In most instances, administration willresult in the release of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof into the bloodstream.

In specific embodiments, it may be desirable to administer(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof locally. This may be achieved,for example, and not by way of limitation, by local infusion duringsurgery, topical application, e.g., in conjunction with a wound dressingafter surgery, by injection, by means of a catheter, by means of asuppository, or by means of an implant, said implant being of a porous,non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers.

In certain embodiments, it may be desirable to introduce(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof into the central nervous systemby any suitable route, including intraventricular, intrathecal andepidural injection. Intraventricular injection may be facilitated by anintraventricular catheter, for example, attached to a reservoir, such asan Ommaya reservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof can be formulated as asuppository, with traditional binders and vehicles such astriglycerides.

In another embodiment,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof can be delivered in a vesicle,in particular a liposome (see Langer, 1990, Science 249:1527–1533; Treatet al., in Liposomes in the Therapy of Infectious Disease and Cancer,Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353–365 (1989);Lopez-Berestein, ibid., pp. 317–327; see generally ibid.).

In yet another embodiment,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof can be delivered in acontrolled-release system (see, e.g., Goodson, in Medical Applicationsof Controlled Release, supra, vol. 2, pp. 115–138 (1984)). Othercontrolled-release systems discussed in the review by Langer, 1990,Science 249:1527–1533) may be used. In one embodiment, a pump may beused (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng.14:201; Buchwald et al., 1980, Surgery 88:507 Saudek et al., 1989, N.Engl. J. Med. 321:574). In another embodiment, polymeric materials canbe used (see Medical Applications of Controlled Release, Langer and Wise(eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled DrugBioavailability, Drug Product Design and Performance, Smolen and Ball(eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol.Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989,J. Neurosurg. 71:105). In yet another embodiment, a controlled-releasesystem can be placed in proximity of a target of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof, e.g., the spinal column orbrain, thus requiring only a fraction of the systemic dose.

The present compositions can optionally comprise a suitable amount of apharmaceutically acceptable vehicle so as to provide the form for properadministration to the patient.

In a specific embodiment, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, mammals, and more particularly inhumans. The term “vehicle” refers to a diluent, adjuvant, excipient, orcarrier with which a compound of the invention is administered. Suchpharmaceutical vehicles can be liquids, such as water and oils,including those of petroleum, animal, vegetable or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical vehicles can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea, and the like. In addition,auxiliary, stabilizing, thickening, lubricating and coloring agents maybe used. When administered to a patient, the pharmaceutically acceptablevehicles are preferably sterile. Water is a preferred vehicle when thecompound of the invention is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid vehicles, particularly for injectable solutions.Suitable pharmaceutical vehicles also include excipients such as starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol and thelike. The present compositions, if desired, can also contain minoramounts of wetting or emulsifying agents, or pH buffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the pharmaceutically acceptable vehicle is acapsule (see e.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical vehicles are described in Remington 's PharmaceuticalSciences, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19thed., 1995, pp. 1447 to 1676, incorporated herein by reference.

In a preferred embodiment,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is formulated in accordancewith routine procedures as a pharmaceutical composition adapted for oraladministration to human beings. Compositions for oral delivery may be inthe form of tablets, lozenges, aqueous or oily suspensions, granules,powders, emulsions, capsules, syrups, or elixirs, for example. Orallyadministered compositions may contain one or more agents, for example,sweetening agents such as fructose, aspartame or saccharin; flavoringagents such as peppermint, oil of wintergreen, or cherry; coloringagents; and preserving agents, to provide a pharmaceutically palatablepreparation. Moreover, where in tablet or pill form, the compositionscan be coated to delay disintegration and absorption in thegastrointestinal tract thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compositions. In these later platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral compositions can includestandard vehicles such as mannitol, lactose, starch, magnesium stearate,sodium saccharin, cellulose and magnesium carbonate. Such vehicles arepreferably of pharmaceutical grade. Typically, compositions forintravenous administration comprise sterile isotonic aqueous buffer.Where necessary, the compositions may also include a solubilizing agent.

In another embodiment,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof can be formulated forintravenous administration. Compositions for intravenous administrationmay optionally include a local anesthetic such as lignocaine to lessenpain at the site of the injection. Generally, the ingredients aresupplied either separately or mixed together in unit dosage form, forexample, as a dry lyophilized powder or water free concentrate in ahermetically sealed container such as an ampoule or sachette indicatingthe quantity of active agent. Where(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is to be administered byinfusion, it can be dispensed, for example, with an infusion bottlecontaining sterile pharmaceutical grade water or saline. Where the(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is administered by injection,an ampoule of sterile water for injection or saline can be provided sothat the ingredients may be mixed prior to administration.

The amount of (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof that will be effective in thetreatment of a particular disorder or condition disclosed herein willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques. In addition, in vitro or in vivo assaysmay optionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed will also depend on the route ofadministration, and the seriousness of the disease or disorder, andshould be decided according to the judgment of the practitioner and eachpatient's circumstances. However, suitable dosage ranges for oraladministration are generally about 0.001 milligram to about 200milligrams of (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof per kilogram body weight perday. In specific embodiments of the invention, the oral dose is about0.01 milligram to about 100 milligrams per kilogram body weight per day,more preferably about 0.1 milligram to about 75 milligrams per kilogrambody weight per day, more preferably about 0.5 milligram to about 50milligrams per kilogram body weight per day, and yet more preferablyabout 1 milligram to about 30 milligrams per kilogram body weight perday. In another embodiment, the oral dose is about 1 milligram to about3 milligrams of (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane ora pharmaceutically acceptable salt thereof per kilogram body weight perday. In another embodiment, the oral dose is about 0.1 milligram toabout 2 milligrams of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof per kilogram body weight one totwo times per day. The dosage amounts described herein refer to totalamounts administered; that is, if(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and/or one or morepharmaceutically acceptable salts thereof are administered, thepreferred dosages correspond to the total amount administered. Oralcompositions preferably contain about 10% to about 95% active ingredientby weight.

Suitable dosage ranges for intravenous (i.v.) administration are about0.01 milligram to about 100 milligrams per kilogram body weight per day,about 0.1 milligram to about 35 milligrams per kilogram body weight perday, and about 1 milligram to about 10 milligrams per kilogram bodyweight per day. Suitable dosage ranges for intranasal administration aregenerally about 0.01 pg/kg body weight per day to about 1 mg/kg bodyweight per day. Suppositories generally contain about 0.01 milligram toabout 50 milligrams of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof per kilogram body weight perday and comprise active ingredient in the range of about 0.5% to about10% by weight.

Recommended dosages for intradermal, intramuscular, intraperitoneal,subcutaneous, epidural, sublingual, intracerebral, intravaginal,transdermal administration or administration by inhalation are in therange of about 0.001 milligram to about 200 milligrams per kilogram ofbody weight per day. Suitable doses for topical administration are inthe range of about 0.001 milligram to about 1 milligram, depending onthe area of administration. Effective doses may be extrapolated fromdose-response curves derived from in vitro or animal model test systems.Such animal models and systems are well known in the art.

The invention also provides pharmaceutical packs or kits comprising oneor more vessels containing(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof. Optionally associated withsuch container(s) can be a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, use or sale for human administration. In acertain embodiment, the kit contains(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and/or one or morepharmaceutically acceptable salts thereof. In another embodiment, thekit comprises a therapeutic agent and(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof.

(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof are preferably assayed invitro or in vivo, for the desired therapeutic or prophylactic activity,prior to use in humans. For example, in vitro assays can be used todetermine whether it is preferable to administer(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, a pharmaceuticallyacceptable salt thereof, and/or another therapeutic agent. Animal modelsystems can be used to demonstrate safety and efficacy.

Other methods will be known to the skilled artisan and are within thescope of the invention.

4.5 Combination Therapy

In certain embodiments of the present invention,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof can be used in combinationtherapy with at least one other therapeutic agent.(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof and the other therapeutic agentcan act additively or, more preferably, synergistically. In a preferredembodiment, (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is administered concurrentlywith the administration of another therapeutic agent, which can be partof the same composition as or in a different composition from thatcomprising (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof. The other therapeutic agentcan be useful for treating and/or preventing (as defined herein) asecondary malady resulting from a disorder alleviated by inhibitingdopamine reuptake. In another embodiment,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is administered prior orsubsequent to administration of another therapeutic agent. As many ofthe disorders for which(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof are useful in treating arechronic, in one embodiment combination therapy involves alternatingbetween administering a composition comprising a(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof and a composition comprisinganother therapeutic agent. The duration of administration of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, a pharmaceuticallyacceptable salt thereof, or the other therapeutic agent can be, e.g.,one month, three months, six months, a year, or for more extendedperiods, such as the patient's lifetime. In certain embodiments, when(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is administered concurrentlywith another therapeutic agent that potentially produces adverse sideeffects including, but not limited to, toxicity, the other therapeuticagent can advantageously be administered at a dose that falls below thethreshold at which the adverse side effect is elicited.

The other therapeutic agent can be an anti-attention-deficit-disorderagent. Useful anti-attention-deficit-disorder agents include, but arenot limited to, methylphenidate; dextroamphetamine; tricyclicantidepressants, such as imipramine, desipramine, and nortriptyline; anda psychostimulant, such as pemoline and deanol.

The other therapeutic agent can be an anti-addictive-disorder agent.Useful anti-addictive-disorder agents include, but are not limited to,tricyclic antidepressants; MAO inhibitors; glutamate antagonists, suchas ketamine HCl, dextromethorphan, dextrorphan tartrate and dizocilpine(MK801); degrading enzymes, such as anesthetics and aspartateantagonists; GABA agonists, such as baclofen and muscimol HBr; reuptakeblockers; degrading enzyme blockers; glutamate agonists, such asD-cycloserine, carboxyphenylglycine, L-glutamic acid, andcis-piperidine-2,3-dicarboxylic acid; aspartate agonists; GABAantagonists such as gabazine (SR-95531), saclofen, bicuculline,picrotoxin, and (+) apomorphine HCl; and dopamine antagonists, such asspiperone HCl, haloperidol, and (−) sulpiride.

The other therapeutic agent can be an anti-alcohol agent. Usefulanti-alcohol agents include, but are not limited to, disulfiram andnaltrexone.

The other therapeutic agent can be an anti-nicotine agent. Usefulanti-nicotine agents include, but are not limited to, clonidine.

The other therapeutic agent can be an anti-opiate agent. Usefulanti-opiate agents include, but are not limited to, methadone,clonidine, lofexidine, levomethadyl acetate HCl, naltrexone, andbuprenorphine.

The other therapeutic agent can be an anti-cocaine agent. Usefulanti-cocaine agents include, but are not limited to, desipramine,amantadine, fluoxidine, and buprenorphine.

The other therapeutic agent can be an appetite suppressant. Usefulappetite suppressants include, but are not limited to, fenfluramine,phenylpropanolamine, and mazindol.

The other therapeutic agent can be an anti-lysergic acid diethylamide(“anti-LSD”) agent. Useful anti-LSD agents include, but are not limitedto, diazepam.

The other therapeutic agent can be an anti-phencyclidine (“anti-PCP”)agent. Useful anti-PCP agents include, but are not limited to,haloperidol.

The other therapeutic agent can be an anti-Parkinson's-disease agent.Useful anti-Parkinson's-disease agents include, but are not limited to,dopamine precursors, such as levodopa, L-phenylalanine, and L-tyrosine;neuroprotective agents; dopamine agonists; dopamine reuptake inhibitors;anticholinergics such as amantadine and memantine; and1,3,5-trisubstituted adamantanes, such as1-amino-3,5-dimethyl-adamantane (U.S. Pat. No. 4,122,193 to Sherm etal.).

The other therapeutic agent can be an anti-depression agent. Usefulanti-depression agents include, but are not limited to, amitriptyline,clomipramine, doxepine, imipramine, trimipramine, amoxapine,desipramine, maprotiline, nortriptyline, protripyline, fluoxetine,fluvoxamine, paroxetine, setraline, venlafaxine, bupropion, nefazodone,trazodone, phenelzine, tranylcypromine and selegiline.

The other therapeutic agent can be an anxiolytic agent. Usefulanxiolytic agents include, but are not limited to, benzodiazepines, suchas alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam,halazepam, lorazepam, oxazepam, and prazepam; non-benzodiazepine agents,such as buspirone; and tranquilizers, such as barbituates.

The other therapeutic agent can be an antipsychotic drug. Usefulantipsychotic drugs include, but are not limited to, phenothiazines,such as chlorpromazine, mesoridazine besylate, thioridazine,acetophenazine maleate, fluphenazine, perphenazine, and trifluoperazine;thioxanthenes, such as chlorprothixene, and thiothixene; and otherhetercyclic compounds, such as clozapine, haloperidol, loxapine,molindone, pimozide, and risperidone. Preferable anti-psychotic drugsinclude chlorpromazine HCl, thioridazine HCl, fluphenazine HCl,thiothixene HCl, and molindone HCl.

The other therapeutic agent can be an anti-obesity drug. Usefulanti-obesity drugs include, but are not limited, to β-adrenergicreceptor agonists, preferably β-3 receptor agonists such as, but notlimited to, fenfluramine; dexfenfluramine; sibutramine; bupropion;fluoxetine; phentermine; amphetamine; methamphetamine;dextroamphetamine; benzphetamine; phendimetrazine; diethylpropion;mazindol; phenylpropanolamine; norepinephrine-serotonin reuptakeinhibitors, such as sibutramine; and pancreatic lipase inhibitors, suchas orlistat.

5. EXAMPLE (−)-1-(3,4-DICHLOROPHENYL)-3-AZABICYCLO[3.1.0]HEXANEHydrochloride

To 279 mg of (±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexanehydrochloride obtained using the methods described in Epstein et al., J.Med. Chem., 24:481–490 (1981) was added 7 mL of 9:1 hexane:isopropylalcohol, followed by 8 drops of diethylamine. To the resulting mixturewas added isopropyl alcohol, dropwise, until a solution was obtained.The solution was concentrated to a volume of 6 mL using a stream ofhelium gas, and six 1-mL portions of the concentrate were subjected tohigh-performance liquid chromatography using an HPLC instrument equippedwith a 1 cm×25 cm Daicel CHIRALPAK AD column (Chiral Technologies, Inc.,Exton, Pa.). Elution was carried out at ambient temperature using 95:5(v/v) hexane:isopropyl alcohol solution containing 0.05% diethylamine asa mobile phase at a flow rate of 6 mL/min. The fraction eluting at about26.08 to 34 minutes was collected and concentrated to provide a firstresidue, which was dissolved in a minimal amount of ethyl acetate. Usinga stream of nitrogen, the ethyl acetate solution was evaporated toprovide a second residue, which was dissolved in 1 mL of diethyl ether.To the diethyl ether solution was added 1 mL diethyl ether saturatedwith gaseous hydrochloric acid. A precipitate formed, which wasfiltered, washed with 2 mL of diethyl ether and dried to provide 33 mgof (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride of88% enantiomeric excess. This material was repurified using thechromatography conditions described above. The fraction eluting at about28 to about 34 minutes was concentrated, acidified, and dried, asdescribed above, to provide 16.0 mg of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride:optical rotation [α]²⁵ _(D)=−56° in methanol at 2 mg/mL; 99.1%enantiomeric excess.

6. EXAMPLE Activity Comparison of(−)-1-(3,4-DICHLOROPHENYL)-3-AZABICYCLO[3.1.0]HEXANE HCL and(+)-1-(3,4-DICHLOROPHENYL)-3-AZABICYCLO[3.1.0]HEXANE HCL in a Dopamine,Norepinephrine, and Serotonin Transporter Binding Assay

Dopamine, norepinephrine, and serotonin uptake-inhibition activity of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride wascompared to that of (±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexanehydrochloride using a standard dopamine transporter binding assay.

6.1 Materials and Methods

6.1.1 Dopamine Transporter Assay

The dopamine uptake transporter binding assay was performed according tothe methods described in Madras et al., 1989, Mol. Pharmacol.36(4):518–524 and Javitch et al., 1984, Mol. Pharmacol. 26(1):35–44. Thereceptor source was guinea pig striatal membranes; the radioligand was[³H]WIN 35,428 (DuPont-NEN, Boston, Mass.) (60–87 Ci/mmol) at a finalligand concentration of 2.0 nM; the non-specific determinant 1 μM1-[2-[bis(4-Fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazinedihydrochloride (“GBR 12909”), a high-affinity dopamine uptakeinhibitor; reference compound was also GBR 12909.(−)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl was obtainedaccording to the method of Example 5, above. Reactions were carried outin 50 mM TRIS-HCl (pH 7.4), containing 120 mM NaCl and at 0° C. to 4° C.for two hours. The reaction was terminated by rapid vacuum filtrationonto glass fiber filters. Radioactivity trapped in the filters wasdetermined and compared to control values in order to ascertain theinteractions of the test compound with the dopamine uptake site. Thedata are reported in Table 1 below.

6.1.2 Norepinephrine Transporter Assay

The norepinephrine transporter binding assay was performed according tothe methods described in Raisman et al., 1982, Eur. Jrnl. Pharmacol.78:345–351 and Langer et al., 1981, Eur. Jrnl. Pharmacol. 72:423. Thereceptor source was rat forebrain membranes; the radioligand was[³H]nisoxetine (60–85 Ci/mmol) at a final ligand concentration of 1.0nM; the non-specific determinant 1 μM desipramine (“DMI”), ahigh-affinity norepinephrine uptake inhibitor; reference compound wasdesipramine (“DMI”), imipramine, amitriptyline, or nisoxetine.(−)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl was obtainedaccording to the method of Example 5, above. Reactions were carried outin 50 mM TRIS-HCl (pH 7.4), containing 300 mM NaCl and 5 mM KCl and at0° C. to 4° C. for four hours. The reaction was terminated by rapidvacuum filtration onto glass fiber filters. Radioactivity trapped in thefilters was determined and compared to control values in order toascertain the interactions of the test compound with the norepinephrineuptake site. The data are reported in Table 2 below.

6.1.3 Serotonin Transporter Assay

The serotonin transporter binding assay was performed according to themethods described in D'Amato et al., 1987, Jrnl. Pharmacol. & Exp. Ther.242:364–371 and Brown et al., 1986, Eur. Jrnl. Pharmacol. 123:161–165.The receptor source was human platelet membranes; the radioligand was[³H]citalopram (70–87 Ci/mmol) at a final ligand concentration of 0.7nM; the non-specific determinant 1 μM clomipramine, a high-affinityserotonin uptake inhibitor; reference compound was imipramine.(−)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl was obtainedaccording to the method of Example 5, above. Reactions were carried outin 50 mM TRIS-HCl (pH 7.4), containing 120 mM NaCl and 5 mM KCl and at25° C. for one hour. The reaction was terminated by rapid vacuumfiltration onto glass fiber filters. Radioactivity trapped in thefilters was determined and compared to control values in order toascertain the interactions of the test compound with the serotoninuptake site. The data are reported in Table 3 below.

6.2 Results

TABLE 1 Dopamine Transporter Binding Assay Compound Ki(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl 2.61 × 10⁻⁷(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl 1.54 × 10⁻⁷ GBR12909 1.16 × 10⁻⁸

TABLE 2 Norepinephrine Transporter Binding Assay Compound Ki(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl N/A(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl 1.42 × 10⁻⁷Desimipramine HCl (“DMI”) 1.13 × 10⁻⁹ N/A = no measurable affinity

TABLE 3 Serotonin Transporter Binding Assay Compound Ki(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl N/A(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl 1.87 × 10⁻⁷Imipramine HCl 2.64 × 10⁻⁸ N/A = no measurable affinity

The data in Table 1 show that both(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl and(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl have affinityfor the dopamine uptake site. Conversely, the data in Tables 2 and 3show that the (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HClhas affinity for the norepinephrine and serotonin uptake sites, whereinthe (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl has nomeasurable affinity for the norepinephrine and serotonin uptake sites.Although the (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HClhas a higher binding affinity for the dopamine reuptake site than the(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl, the use of the(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl can be moreadvantageous than the(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl for inhibitingdopamine uptake because of its specificity for inhibiting dopamineuptake. In other words, the use of the(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl can preventundesirable side effects associated with inhibiting norepinephrineuptake and serotonin uptake, such as hypertension and sexualdysfunction, respectively.

Successful inhibition of dopamine reuptake has been has been associatedwith the treatment of attention deficit disorder, depression, obesity,Parkinson's disease, a tic disorder and an addictive disorder (Hitri etal., 1994, Clin. Pharmacol. 17:1–22; Noble, 1994, Alcohol Supp. 2:35–43;and Blum et al., 1995, Pharmacogenetics 5:121–141). Because of itsspecificity for inhibiting dopamine uptake,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof that is more advantageous than(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof for treating or preventing adisorder alleviated by inhibiting dopamine reuptake in a patient.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of whichare incorporated herein by reference.

1. A method for treating a disorder alleviated by inhibiting dopaminereuptake, wherein the disorder is selected from the group consisting ofattention deficit disorder, depression, obesity, Parkinson's disease,and a tic disorder, comprising administering to a patient in need ofsuch treatment or prevention an effective amount of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof, each being substantially freeof its corresponding (+)-enantiomer.
 2. The method according to claim 1,wherein the attention-deficit disorder is selected from the groupconsisting of attention-deficit/hyperactivity disorder, predominatelyinattentive type; attention-deficit/hyperactivity disorder,predominately hyperactivity-impulsive type;attention-deficit/hyperactivity disorder, combined type; conductdisorder; and oppositional defiant disorder.
 3. The method according toclaim 1, wherein the depression is selected from the group consisting ofmajor depressive disorder, recurrent; dysthymic disorder; and majordepressive disorder, single episode.
 4. The method according to claim 1,wherein the Parkinson's disease is neuroleptic-induced parkinsonism. 5.The method according to claim 1, wherein the tic disorder is selectedfrom the group consisting of Tourette's disorder, chronic motordisorder, vocal tic disorder, transient tic disorder, stuttering,autistic disorder, and somatization disorder.
 6. A method for treatingattention-deficit disorder alleviated by inhibiting dopamine reuptake,comprising administering to a patient in need of such treatment orprevention an effective amount of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof, each being substantially freeof its corresponding (+)-enantiomer.
 7. The method according to claim 6,wherein the (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane orpharmaceutically acceptable salt thereof has no more than about 2% w/wof the corresponding (+)-enantiomer.
 8. The method according to claim 6,wherein the (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane orpharmaceutically acceptable salt thereof has no more than about 1% w/wof the corresponding (+)-enantiomer.
 9. The method according to claim 6,wherein the attention-deficit disorder is selected from the groupconsisting of attention-deficit/hyperactivity disorder, predominatelyinattentive type; attention-deficit/hyperactivity disorder,predominately hyperactivity-impulsive type;attention-deficit/hyperactivity disorder, combined type; conductdisorder; and oppositional defiant disorder.
 10. A method for treatingdepression alleviated by inhabiting dopamine reutake, comprisingadministering to a patient in need of such treatment or prevention aneffective amount of (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexaneor a pharmaceutically acceptable salt thereof, each being substantiallyfree of its corresponding (+)-enantiomer.
 11. The method according toclaim 10, wherein the(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or pharmaceuticallyacceptable salt thereof has no more than about 2% w/w of thecorresponding (+)-enantiomer.
 12. The method according to claim 10,wherein the (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane orpharmaceutically acceptable salt thereof has no more than about 1% w/wof the corresponding (+)-enantiomer.
 13. The method according to claim10, wherein the depression is selected from the group consisting ofmajor depressive disorder, recurrent; dysthymic disorder; and majordepressive disorder, single episode.
 14. A method for treating obesity,alleviated by inhibiting dopamine reutake, comprising administering to apatient in need of such treatment or prevention an effective amount of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof, each being substantially freeof its corresponding (+)-enantiomer.
 15. The method according to claim14, wherein the (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane orpharmaceutically acceptable salt thereof has no more than about 2% w/wof the corresponding (+)-enantiomer.
 16. The method according to claim14, wherein the (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane orpharmaceutically acceptable salt thereof has no more than about 1% w/wof the corresponding (+)-enantiomer.
 17. A method for treatingParkinson's disease alleviated by inhibiting dopamine reutake,comprising administering to a patient in need of such treatment orprevention an effective amount of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof, each being substantially freeof its corresponding (+)-enantiomer.
 18. The method according to claim17, wherein the (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane orpharmaceutically acceptable salt thereof has no more than about 2% w/wof the corresponding (+)-enantiomer.
 19. The method according to claim17, wherein the (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane orpharmaceutically acceptable salt thereof has no more than about 1% w/wof the corresponding (+)-enantiomer.
 20. A method for treating a ticdisorder, alleviated by inhibiting dopamine reutake, comprisingadministering to a patient in need of such treatment or prevention aneffective amount of (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexaneor a pharmaceutically acceptable salt thereof, each being substantiallyfree of its corresponding (+)-enantiomer.
 21. The method according toclaim 20, wherein the(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or pharmaceuticallyacceptable salt thereof has no more than about 2% w/w of thecorresponding (+)-enantiomer.
 22. The method according to claim 20,wherein the (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane orpharmaceutically acceptable salt thereof has no more than about 1% w/wof the corresponding (+)-enantiomer.
 23. The method according to claim20, wherein the tic disorder is selected from the group consisting ofTourette's disorder, chronic motor disorder, vocal tic disorder,transient tic disorder, stuttering, autistic disorder, and somatizationdisorder.